b) Drug release from intelligent gels responding to antibody concentration.
There are numerous kinds of bioactive compounds which exist in the body. Recently, novel gels were developed which responded to the change in conbecentration of bioactive compounds to alter their swelling/deswelling characteristics. Miyata and co-workers [57-58] focused on the introduction of stimuli-responsive cross-linking structures into hy-drogels. Special attention was given to antigen antibody complex formation as the cross-linking units in the gel, because specific antigen recognition of an antibody can provide the basis for a new device fabrication.

c) Electric stimuli-responsive pulsatile release
The combination of developments in several technologies, such as microelectronics and micromachin ing, as well as the potential need for chronotherapy, have currently assisted the development of electronically assisted drug delivery technologies. These technologies include iontophoresis, infusion pumps, and sonophoresis [59]. Several approaches have also been presented in the literature describing the preparation of electric stimuli-responsive drug delivery systems using hydrogels.
Kishi et al. [60] developed an electric stimuli induced drug release system using the electrically stimulated swelling /deswelling characteristics of polyelectrolyte hydrogels. They utilized a chemomechanical system, which contained a drug model within the polyelectrolyte gel structure. These gels exhibited reversible swelling / shrinking behavior in response to on–off switching of an electric stimulus. Thus, drug molecules within the polyelectrolyte gels might be squeezed out from the electric stimuli-induced gel contraction along with the solvent flow. To realize this mechanism, poly(sodium acrylate) microparticulate gels containing pilocarpine as a model drug were prepared. [61]

 Nowadays pulsatile drug delivery systems are gaining importance in various disease conditions specifically in diabetes where dose is required at different time intervals. Among these systems, multi-particulate systems (e.g. pellets) offer various advantages over single unit which include no risk of dose dumping, flexibility of blending units with different release patterns, as well as short and reproducible gastric residence time [62]. Multiparticulate systems consists pellets of different release profile which can be of any type like time dependent, pH dependent, micro flora activated system as discussed in the previous sections. Site and time specific oral drug delivery have recently been of great interest in pharmaceutical field to achieve improved therapeutic efficacy. Gastroretentive drug delivery system is an approach to prolong gastric residence time, thereby targeting sitespecific drug release in upper gastrointestinal (GI) tract. Floating drug delivery system (FDDS) and bioadhesive drug delivery are widely used techniques for gastro retention. Low density porous multiparticulate systems have been used by researchers for formulation of FDDS. Sharma and Pawar developed multiparticulate floating pulsatile drug delivery system using porous calcium silicate and sodium alginate for time and site specific drug release of meloxicam [63]. Various pulsatile technologies have been developed on the basis of methodologies as discussed previously. These includes OROS® technology, CODAS® technology, CEFORM® technology, DIFFUCAPS® technology, Three-dimensional printing®, timerx® etc.

Now a day's pulsatile drug delivery is gaining popularity. The prime advantage in this drug delivery is that drug is released when necessity comes. As a result chance of development of drug resistance which is seen in conventional and sustained release formulations can be reduced. Furthermore, some anticancer drugs are very toxic. These drugs give hazardous problems in conventional and sustained release therapies. Now many FDA approved chronotherapeutic drugs are available in the market. This therapy is mainly applicable where sustained action is not required and drugs are toxic. Key point of development of this formulation is to find out circadian rhythm i.e. suitable indicator which will trigger the release of drug from the device. Another point is absence of suitable rhythmic biomaterial which should be biodegradable, biocompatible and reversibly responsive to specific biomarkers in rhythmic manner. Regulatory is another big question. In preapproval phase it is sometimes difficult to show chronotherapeutic advantage in clinical settings. In postapproval phase causal recreational drug abuse along with on a much larger scale, by the criminal diversion of these modified formulations for profit have arisen problems. The FDA has now heavily relied on the development and implementation of risk management programs as a strategy to allow an approval of a drug to go forward while exercising some restrictions. Many researches are going on the pulsatile drug delivery to discover circadian rhythm with suitable device in the world. In future this delivery will be a leading way to deliver therapeutic agents due to its some unique characters like low chance of dose dumping, patient compliance and the above factors. [64]

1. Extended daytime or nighttime activity
2. Reduced side effects
3. Reduced dosage frequency
4. Reduction in dose size
5. Improved patient compliance
6. Lower daily cost to patient due to fewer dosage units are required by the patient in therapy.
7. Drug adapts to suit circadian rhythms of body functions or diseases.
8. Drug targeting to specific site like colon.
9. Protection of mucosa from irritating drugs.
10. Drug loss is prevented by extensive first pass metabolism .
11. Patient comfort and compliance: Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance.

Pulsatile drug deleivery system have certain limitation, so in many cases these drug delivery system is fails,
• Multiple manufacturing steps in case of Multiparticulate pulsatile drug delivery system.
• Low drug load
• Incomplete release
• In-vivo variability in single unit pulsatile drug delivery system.

1. Janugade BU, Patil SS, Patil SV, Lade PD: Pulsatile drug delivery system for chronopharmacological disorders: an overview. Journal of Pharmacy Research , 2009; 2 (1):133-143.
2. Ramesh D. Parmar, Rajesh K. Parikh, G. Vidyasagar, Dhaval V. Patel, Chirag J. Patel and Biraju D. Patel: Pulsatile Drug Delivery Systems: An Overview International Journal of Pharmaceutical Sciences and Nanotechnology 2009; 2(3): 605-607.
3. Nitin Saigal, Sanjula Baboota, Alka Ahuja and Javed Ali: Site Specific Chronotherapeutic Drug Delivery Systems: A Patent Review. Recent Patents on Drug Delivery & Formulation 2009; 3: 64-70.
4. Jha N, Bapat S: Chronobiology and chronotherapeutics. Kathmandu University Med. Jour. 2004; 2(8): 384-388.
5. Bruguolle B, Lemmer B: Recent advances in chronopharmacokinetics: methodological problems, Life Sci. 1993; 52 (23): 1809-1824.
6. Feat/ACF2F15.cfm&pub_id, accesed on 15/9/10.
7. Botti B, Youan C: Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery, Jorn. Control. Rel. 2004; 98(3): 337-353.
8. assessed on 1-2-2011
9.  assessed on 1-2-2011
10. Gothoskar AV, Joshi AM, Joshi NH: Pulsatile Drug Delivery Systems: A Review. Drug Del. Tech. 2004; 4: 5-8.
11. Skloot, G.: Nocturnal Asthma: Mechanisms and Management. The Mount Sinai J. of Med. 2002; 69: 140-147.
12. Survase S, Kumar N: Pulsatile Drug Delivery: Current Scenario. Current Research & Information on Pharmaceutical Sciences. 2007; 8(2): 27-33.
13. Lemmer:  Circadian rhythms and drug delivery. Jou. Control. Rel. 1991; 16: 63-74.
14. Jao F, Wong P, Huynh H, et al. (1992):17
15. Percel P, Vishnupad K and Venkatesh G (2002):13
16.  Katstra WE, Palazzolo RD, Rowe CW, et al. (2000) J. Control. Rel. 66:1-9
17. Stevens HNE, Wilson CG, Welling PG, et al. (2002) Int. J. pharm. 236:27-34
18. Janugade B.U1*, Patil S. S2., Patil S.V. 1, Lade P. D.1 Pulsatile drug delivery system for chronopharmacological disorders: an overview Review Article Journal of Pharmacy Research 2009;2;1:136
19. Neill MC, Rashid A, Stevens HN, GB Patent No. GB2230442, 1993.
20. Sarasija S, Hota A, Colon-specific drug delivery systems, Ind. J. Pharm. Sci., 62(1), 2002, 1-8.
21. Kinget R, Kalala W, Vervoort L, Mooter GV, Colonic drug targeting, J. Drug Targeting, 6(2), 1998, 129-149.
22. Krögel I, Bodmeier R, Pulsatile drug release from an insoluble capsule body controlled by an erodible plug, Pharm. Res., 15(3),1998, 474-481.
23. Krögel I, Bodmeier R, Evaluation of an enzyme-containing capsular shaped pulsatile drug delivery system, Pharm. Res.16 (9), 1999, 1424-1429.
24. Wu F, Zhang ZR, He WL, Zhang Y, Preparation and in vitro release of tetramethylpyrazine phosphate pulsincap capsule controlled by an erodible plug. Yao Xue Xue Bao., 37(9), 2002, 733-738.
25. Crison JR., Siersma PR, Amidon GL, A novel programmable oral release technology for delivering drugs: human feasibility testing using gamma scintigraphy, Proceed Intern Symp Control Rel. Bioact. Mater., 23, 1996, 51-52.
26. Pollock DC, Dong L, Wong P, A new system to deliver a delayed bolus of liquid drug formulation, Proceed Intern Symp, Control. Rel. Bioact. Mater., 28, 2001, 6033.
27. Linkwitz A, Magruder JA, Merrill S, Osmotically Driven Delivery Device with Expandable Orifice for Pulsatile Delivery Effect, US Patent No. 5,318,558, 1994.
28. Linkwitz A., Magruder JA, Merrill S, Osmotically Driven Delivery Device with Expandable Orifice for Pulsatile Delivery Effect, US Patent No. 5,221,278, 1993.
29. Balaban SM, Pike JB, Smith JP, Baile CA, Osmotically Driven Delivery Devices with Pulsatile Effect, US Patent No. 5209746, 1993.
30. Magruder PR, Barclay B, Wong PS, Theeuwes F, Composition Comprising Salbutamol, US Patent No. 4751071, 1988.
31. Magruder PR, Barclay B, Wong PS, Theeuwes F, Constant Release System with Pulsed Release, US Patent No. 4777049, 1988.
32. Magruder PR., Barclay B, Wong PS, Theeuwes F, Composition Comprising a Therapeutic Agent and a Modulating Agent. US Patent No. 4851229, 1989.
33. Gazzaniga A, Iamartino P, Maffione G, Sangalli ME, Oral delayed- release system for colonic specific delivery, Int. J. Pharm., 2(108), 1994, 77-83.
34. Gazzaniga A, Sangalli ME, Giordano F. Oral chronotopic drug delivery systems: achievement of time and/or site specifity, Eur. J. Biopharm., 1994; 40(4): 246-250.
35. Gazzaniga A, Busetti C, Moro L, Crimella T, Sangalli ME, Giordano F. Evaluation of low viscosity HPMC as retarding coating material in the preparation of a time-based oral colon specific delivery system. Proceed Intern Symp Control. Rel. Bioact. Mater., 1995; 22: 242-243.
36. Poli S, Busetti C, Moro L: Oral Pharmaceutical Composition for Specific Colon Delivery, EP Patent No. 0,572,942, 1993.
37. Sangalli ME, Maroni A, Zema L, Busetti C, Giordano F, Gazzaniga A: In vitro and in vivo evaluation of an oral system for time and/or site-specific drug delivery. J. Control. Rel., 2001; 73: 103-110.
38. Maroni A, Sangalli ME, Cerea M, Busetti C, Giordano F, Gazzaniga A: Low viscosity HPMC coating of soft and hard gelatin capsules for delayed and colonic release: preliminary investigations on process parameters and in vitro release performances. Proceed Int. Control. Rel. Bioact. Mater., 1999; 26: 887-888.
39. Patel G: Specialized chronotherapeutic drug delivery systems,
40. Conte U, Colombo P, Manna A, Gazzaniga A: A new ibuprofen pulsed release oral dosage form. Drug Dev. Ind. Pharm., 1989; 15(14- 16): 2583-2596.
41. Conte U, Manna A, Colombo P: Tablet for Pharmaceutical Use Able to Release Active Substances at Successive Times, US Patent No. 4,865,849, 1989.
42. Conte U, Giunchedi P, Maggi L, Sangalli ME, Gazzaniga A, Colombo P, Manna A, Ibuprofen delayed release dosage forms: a proposal for the preparation of an in vitro/in vivo pulsatile system, Eur. J. Pharm., 1992; 38(6):  209-212.
43. Krögel I, Bodmeier R: Floating or pulsatile drug delivery systems based on coated effervescent cores. Int. J. Pharm., 1999; 187: 175-184.
44. Ueda Y, Hata T, Yamaguchi H, Ueda S, Kotani M: Time Controlled Explosion System and Process for Preparation for the Same, US Patent No. 4,871,549, 1989.
45. Ueda Y, Hata T, Yamaguchi H, Kotani M, Ueda S: Development of a novel drug release system, time-controlled explosion system (TES), Part 1: concept and design. J. Drug Targeting. 1994; 2: 35-44.
46. Ueda S, Yamaguchi H, Kotani M, Kimura S, Tokunaga Y, Kagayama A, Hata T: Development of a novel drug release system, time-controlled explosion system (TES), Part II: design of multiparticulate TES and in vitro drug release properties, Chem. Pharm. Bull., 1994; 42(2): 359-363.
47. Amidon GL, Leesman GD: Pulsatile Drug Delivery System, US Patent No. 1993; 5,229,131.
48. Bodmeier R, Guo X, Sarabia RE, Skultety P: The influence of buffer species and strength on diltiazem HCl release from beads coated with aqueous cationic polymer dispersions, Eudragit RS, RL 30D, Pharm. Res.,1996; 13 (1): 52-56.
49. Beckert TE, Pogarell K, Hack I, Petereit HU: Pulsed drug release with film coatings of Eudragit & Mac226; RS 30D, Proceed Int’l Symp Control. Rel. Bioact. Mater., 1999; 26: 533- 534.
50. T. Okano, N. Yui, M. Yokoyama, R. Yoshida: Advances in Polymeric Systems for Drug Delivery, Gordon and Breach, Yverdon, Switzerland, 1994.
51. Y.H. Bae, T. Okano, S.W. Kim: ‘On–off’ thermocontrol of solute transport. I. Temperature dependence of swelling of N-isopropylacrylamide networks modified with hydrophobic components in water, Pharm. Res. 1991; 8 (4): 531–537.
52. Y.H. Bae, T. Okano, S.W. Kim: ‘On–off’ thermocontrol of solute transport. II. Solute release from thermosensitive hydrogels. Pharm. Res. 1991; 8 (5): 624–628.
53. K. Kataoka, A. Harada, Y. Nagasaki: Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliv. Rev. 2001; 47: 113–131.
54. K. Ishihara, M. Kobayashi, I. Shinohara: Control of insulin permeation through a polymer membrane with responsive function for glucose, Makromol. Chem. Rapid Commun. 1983; 4: 327–331.
55. N. Yui, T. Okano, Y. Sakurai, Inflammation responsive degradation of crosslinked hyaluronic acid gels. J. Control. Release 1992; 22: 105–116.
56. N. Yui, J. Nihira, T. Okano, Y. Sakurai: Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid. J. Control. Release 1993; 25: 133–143.
57. T. Miyata, N. Asami, T. Uragami: A reversibly antigen responsive hydrogel. Nature 1999; 399: 766–769.
58. T. Miyata, N. Asami, T. Uragami: Preparation of an antigen sensitive hydrogel using antigen–antibody bindings, Macro molecules 1999; 32: 2082–2084.
59. B. Berner, S.M. Dinh: Electronically assisted drug delivery: an overview, in: B. Berner, S.M. Dinh (Eds.), Electronically Controlled Drug Delivery, CRC Press, Boca Raton, FL, 1998, pp. 3–7.
60. R. Kishi, M. Hara, K. Sawahata, Y. Osada. Conversion of chemical into mechanical energy by synthetic polymer gels (chemomechanical system), in: D. DeRossi, K. Kajiwara, Y. Osada, A. Yamauchi (Eds.), Polymer Gels — Fundamentals and Biomedical Applications, Plenum Press, New York, 1991, pp. 205–220.
61. I.C. Kwon, Y.H. Bae, T. Okano, B. Berner, S.W. Kim: Stimuli sensitive polymers for drug delivery systems. Makro mol. Chem. Macromol. Symp. 1990; 33: 265–277.
62. Dashevsky A and Mohamad A: Int. J. pharm. 2006; 318: 124-131.
63. Sharma S and Pawar A.Int. J. pharm. 2006;  313
64. Asim Sattwa Mandal, Nikhil Biswas, Kazi Masud Karim, Arijit Guha, Sugata Chatterjee, Mamata Behera, Ketousetuo Kuotsu: Drug delivery system based on chronobiology. A review Journal of Controlled Release 2010;10
65. Sunil kamboj, G D Gupta, Jagmohan Oberoy: Matrix Tablets : An Important Tool for Oral Controlled-Release Dosage Forms, Pharmainfo net 2009; 7 (6), 1-9.
66. Rathod Shruti:  Colon Targeted Pulsatile Drug Delivery : A Review. Pharmainfo net 2007; 5(2), 1-11.

palak motan
Joined: 2010-06-06
re pulsatile delivery of antibiotic

sir, your article was very informative . sir. i am a M.pharm student and want todo project pulsatile delivery of antibiotic for travelers diarrohea since the dose of drug is 200mg 3 times a day. is my rationale of msking a pulsatile of antibiotic correct ? Please do reply

maheshrag (not verified)
Pulsatile drug delivery

Mr. Palak motan.......for the diseases which follow circadian rhythms, pulsatile drug delivery is in the case of TD there is no need of PDDs. and


Subscribe to RSS headline updates from:
Powered by FeedBurner